Project Description HyPhy (http://www.hyphy.org) is a scriptable software platform designed to enable flexible and powerful analyses of DNA, RNA, codon, amino acid and other types of sequence data in an evolutionary context. Such analyses have become an indispensable component of most research studies that make use of comparative genomic data. Biologists and bioinformaticians increasingly recognize the benefits of molecular evolutionary analyses. Since its initial release in 2001, HyPhy has become a relatively stable and mature product, and has been downloaded by more than 4,500 unique users, integrated into several popular web-based genomic data analysis servers, cited in over 400 peer-reviewed publications and described in three book chapters, in spite of the fact that the development of the package has never been directly funded. This proposal seeks support to improve the quality, performance, reliability, modularity, documentation and feature sets of the HyPhy system. Specific aims can be divided into four major areas: 1. Software engineering, testing, and documentation of the HyPhy codebase. 2. The development of a high-performance engine for phylogenetic maximum likelihood model fitting and inference. 3. Extension of a newly-initiated toolbox for machine learning applications in molecular evolution. 4. Creation and maintenance of a wiki-themed documentation resource. PUBLIC HEALTH RELEVANCE: Project Narrative Molecular evolutionary analyses are central to many aspects of basic, translational, and applied biomedical research. Examples include identifying gene mutations that allow pathogens to evade the immune response; prediction of the structure and function of proteins; estimating the evolutionary relatedness of human or other populations; characterizing the magnitude of selective pressure, either natural or artificial, on genes or species.